Combined CSF1R Inhibition and Sensory Gamma Stimulation Provide Protective Effects in a Mouse Model of Alzheimer’s Disease

The CSF1R inhibitor Plx3397, an FDA-approved treatment for a rare cancer, has been shown to reduce microglia, lower inflammation, and improve synaptic integrity in several mouse models of Alzheimer’s disease (AD). However, the effects of Plx3397 on synaptic and neural function in AD remain largely unknown. Here, we used the 5xFAD mouse model to characterize the effect of Plx3397 treatment. While Plx3397 administration increased synaptic density in 5xFAD mice, it also reduced the percentage of neurons phase-locked to gamma oscillations. This neural decoupling was closely associated with gene expression changes related to synapse organization. These observations prompted us to investigate whether gamma-frequency entrainment could counteract the neural circuit alterations induced by Plx3397 administration. We thus enhanced gamma phase-locking in neurons using non-invasive patterned sensory light stimulation. Remarkably, restoring gamma oscillations improved neural function, reshaped gene expression signatures, and improved learning and memory in Plx3397-treated 5xFAD mice. These findings suggest that CSF1R inhibitors like Plx3397 may benefit from a multimodal approach combining microglial targeting with non-invasive sensory stimulation to support neural physiology and improve cognitive function in AD.